The present invention relates to methods for producing nateglinide (its chemical name: N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine) that is useful as a therapeutic agent for diabetes. More specifically, it relates to methods for producing nateglinide B-type crystals substantially free of H-type crystals.
It is known that nateglinide is useful as a therapeutic agent for diabetes because it effectively lowers blood glucose by oral administration (Japanese Patent Publication No. Hei 4-15221). In this connection, the crystallization has to be carefully conducted under precisely controlled conditions in order to separate H-type crystals and difficulty of such crystallization procedure was problematic (see Japanese Patent No. 2,508,949).
On the other hand, one of crystal polymorphs of nateglinide, B-type crystals, has an advantage in that the B-type crystals can be easily prepared by conducting the crystallization under cooling. However, there is a possibility in that the B-type crystals are transferred to the H-type crystals during the production stage. In fact, when nateglinide was prepared in industrial scale, it was found that H-type crystals were contaminated in the resulting B-type crystals. Regarding nateglinide to be used as a medicine, it is preferable that a contamination of crystal polymorphs be as small as possible. Since the single crystalline form is the best desired, a method for producing B-type crystals of nateglinide by which a pharmaceutical formulation containing the B-type crystal exclusively without allowing other forms of the crystalline polymorphs to coexist has been desired to be developed.